Nemaline Myopathy (NEM2) via the Nebulin (NEB) Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
1772 NEB 81408 81408,81479 $1590 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
1772NEB81408 81408, 81479 $1590 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Mutations in the nebulin gene (NEB) are the most common cause of autosomal recessive nemaline myopathy (NEM). NEM is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia and the presence of nemaline bodies in skeletal muscle fibers. Muscle weakness is typically observed in affected neonates or infants, although later onset cases are reported (Ryan et al. 2001). The most severely affected muscle groups are proximal limb, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NEM is characterized by type 1 fiber predominance and the presence of rod-like structures called nemaline bodies upon Gomori trichrome staining of skeletal muscle (Ryan et al. 2003). Six clinical types of NEM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan 2002). Nebulin gene mutations more often cause typical neonatal onset disease, although NEB mutations have been found in every clinical form of NEM (Lehtokari et al. 2006). Overlap among the six clinical groups is significant, and adults are sometimes diagnosed only after another family member has presented with typical signs.

Genetics

To date, mutations in six genes have been shown to cause nemaline myopathy. Mutations in ACTA1 (NEM3) and NEB (NEM2) are the only relatively common causes, accounting for 15-25% and up to 50%, respectively, of all studied cases (Ryan et al. 2001; North and Ryan. 2002). All reported cases of NEB-associated NEM demonstrate autosomal recessive inheritance (Lehtokari et al. 2006; Lehtokari et al. 2014). In the largest cohort published to date, Lehtokari et al. (2014) identified 212 NEB mutations segregating with autosomal recessive NEM in 159 families. In this study, pathogenic mutations are found in most exons of the NEB gene, including the triplicate region (exons 82-105). The majority of these mutations (Lehtokari et al. 2014) were splice site variants (34%), frameshift mutations (32%), and nonsense mutations (23%). Reported pathogenic missense variants appear to be less common (~7%). The only common NEB mutation is an exon 55 deletion found at a carrier frequency of about 1% among people of Ashkenazi Jewish ancestry (Anderson et. al. 2004).

Clinical Sensitivity - Sequencing with CNV PG-Select

Up to 50% of all known nemaline myopathy cases are caused by mutations in NEB (North and Ryan 2002).

Gross deletions/duplications account for ~4% of all reported NEB mutations (Lehtokari et al. 2014). An exon 55 deletion is the only common deletion found at a carrier frequency of about 1% among people of Ashkenazi Jewish ancestry (Anderson et. al. 2004). A separate PCR based assay for this common deletion is available (#356).

Testing Strategy

This test provides full coverage of all coding exons of the NEB gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Exons 82-105 of the NEB gene are organized in three highly homologous blocks of 8 exons each making this region difficult to analyze by NextGen Sequencing. Due to the homology, there are mapping and alignment issues which may cause variants in this region to go undetected. We employ a novel long-range 2-step PCR with Sanger sequencing to analyze this region of the NEB gene which allows correct exon and zygosity assignment.

Indications for Test

Individuals with symptoms consistent with the typical congenital form of nemaline myopathy. Individuals whose muscle biopsies show predominance of type 1 fibers and nemaline bodies. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in NEB.

Gene

Official Gene Symbol OMIM ID
NEB 161650
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Nemaline Myopathy 2 AR 256030

Related Tests

Name
Nemaline Myopathy Panel
Nemaline Myopathy via the NEB Exon 55 Deletion
Nemaline Myopathy via the NEB Gene, Exons 82-105 (Triplicate Repeat Region)

Citations

  • Anderson SL, Ekstein J, Donnelly MC, Keefe EM, Toto NR, LeVoci LA, Rubin BY. 2004. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 115: 185-190. PubMed ID: 15221447
  • Lehtokari V-L, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA, Donner K, Marttila M, Saunders C, Barth PG, Dunnen JT den, Beggs A, Clarke NF, North KN, Laing NG, Romero NB, Winder TL, Pelin K, Wallgren-Pettersson C. 2014. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies. Hum. Mutat. 35:1418-1426 PubMed ID: 25205138
  • Lehtokari VL, Pelin K, Sandbacka M, Ranta S, Donner K, Muntoni F, Sewry C, Angelini C, Bushby K, Van den Bergh P, Iannaccone S, Laing NG, Wallgren-Pettersson C. 2006. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum Mutat 27: 946-956. PubMed ID: 16917880
  • North KN, Ryan MM. 2002. Nemaline Myopathy. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301465
  • Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Houston R, Muirhead D, Dennett X, Shield LK, Girolami U De, Iannaccone ST, Laing NG, North KN, Beggs AH. 2003. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 60: 665–673. PubMed ID: 12601110
  • Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN. 2001. Nemaline myopathy: a clinical study of 143 cases. Ann. Neurol. 50: 312–320. PubMed ID: 11558787

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

loading Loading... ×

ORDER OPTIONS

View Ordering Instructions

1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Total Price: $
×
Copy Text to Clipboard
×